Endogenous-Activatable Nanotheranostic Platform for Multimodal Bioimaging-Guided Photodynamic and Gas Synergistic Cancer Therapy.

Based on gold nanoclusters (AuNCs), l-Arginine (l-Arg), dendritic macroporous silica nanoparticles (DSiO2), MnO2 nanosheets, and Sgc8 aptamers, a multifunctional nanotheranostic platform (DALMS) was developed for endogenous-activatable multimodal bioimaging-guided synergistic targeted cancer therapy. The DALMS precisely targets cancer cells via Sgc8 and responds to the high concentration GSH in the tumor microenvironment (TME). The subsequent release of AuNCs and l-Arg enables endogenous-activatable, controlled drug delivery. In tumor tissues and cells, DALMS exhibits efficient two-photon near-infrared fluorescence imaging with penetration depths of up to 320 μm, excellent fluorescence lifetime imaging, and sensitive MRI to guide accurate cancer diagnosis. As photosensitizers, as-released AuNCs generate reactive oxygen species (ROS) under long-wavelength laser irradiation, and l-Arg generates nitric oxide (NO) in the TME, resulting in further production of reactive nitrogen species (RNS) with high lethality to kill cancers. The synergistic effect of photodynamic therapy (PDT) and NO gas therapy destroys tumor cells, leading to a survival rate of 13.8% and a tumor inhibition rate of 96.09%. Thus, this DALMS achieves multimodal bioimaging-guided synergistic cancer therapy and significantly enhances the antitumor effect, providing a new strategy for precise diagnosis and effective treatment of cancer.